Thyroid proliferative disorders, ranging from clinically silent nodular hyperplasia to adenomatous goiter, and including thyroid cancer, affect a large part of the United States population, with a higher prevalence in women than in men. Although most nodules are benign, approximately 5% of them develop malignant features, and it is hard to predict the fate of any specific lesion, using only morphological features. Our ability to predict or identify thyroid cancer among the highly prevalent condition of nodular thyroid disease would be greatly improved by the identification of pathways that correlate with increased nodule growth or ongoing thyroid dedifferentiation. Numerous clinical data have recently pointed to the PI3K/PTEN/AKT pathway as a crucial player in thyroid proliferative disorders. The broad, long-term objective of this project is to test the hypotheses that activation of the PI3K/AKT pathway induces a benign thyroid hyperproliferative disorder, that it crosstalks with estrogen signaling to determine a higher proliferation index and increased adenoma incidence in females, and that it facilitates malignant transformation upon development of cooperating genetic alterations. We propose to test these hypotheses through a direct in vivo approach in a genetically defined system, with the following specific aims: Aim 1: To characterize in vivo and ex vivo the functional and molecular alterations induced in the mouse thyroid by the activation of the PI3K/PTEN/AKT axis. Aim 2: To elucidate the mechanisms through which circulating estrogens increase thyrocyte proliferation and adenoma susceptibility in female mutant mice. Aim 3: To test in vivo and ex vivo the hypothesis that PI3K/AKT activation allows thyroid cells to overcome inhibitory feedback signals initiated by Ras activation, thus inducing malignant thyrocyte transformation. PUBLIC HEALTH RELEVANCE: The ultimate challenge in thyroidology is the prediction of thyroid cancer among the highly prevalent condition of nodular thyroid disease. Thus it would be ideal to define pathways that correlate with increased nodule growth or ongoing thyroid transformation. Our preliminary data demonstrate that chronic PI3K activity is sufficient, in vivo, to induce thyroid hyperplasia and to create fertile ground for neoplastic transformation. Consequently we are in a unique position to achieve in vivo a better understanding of the mechanisms responsible for the development of nodular thyroid disease and its progression to thyroid follicular neoplasms.